Enteric hyperoxaluria (EH) is a metabolic disease that results from an excessive absorption of dietary oxalate.
EH occurs mainly in patients with underlying gastrointestinal (GI) disorders, including post gastric bypass surgery, inflammatory bowel disease, Crohn's disease, pancreatitis, and short bowel syndrome.
Increased GI oxalate absorption results in elevated urinary oxalate levels and contributes to kidney stone formation, nephrocalcinosis, crystallopathy and other adverse renal outcomes.
Hyperoxaluria Kidney stones
Objective: Engineer an Escherichia coli Nissle 1917 strain to metabolize oxalate for the treatment for Enteric Hyperoxaluria
Adapted from Immunity, microbiota and kidney disease. Nat Rev. Nephrol 2019.
Engineered EcN has the Potential to Consume Oxalate Throughout the GI Tract
GI Based Therapies Have Demonstrated Lowering of Systemic Oxalate
Dietary Oxalate
Oxalate can be absorbed throughout GI tract.
Stomach
oral enzyme
(i.e. Reloxaliase)
Small
oral enzyme
intestine
(i.e. Reloxaliase)
Colon
colonizing microbes
(i.e. O. formigenes)
SYNB8802
Figure 1: Schematic of SYNB8802. EcN was chromosomally modified to integrate OxlT, ScaaE3, OxdC, and Frc under the control of PfnrS. The thyA and several structural genes within the endogenous prophage were deleted from the genome. Abbreviations: EcN: E. coli Nissle, OxlT = oxalate/formate antiporter; ScaaE3 = oxalyl-CoA synthetase; OxdC = oxalate decarboxylase; FRC = formyl-CoA transferase; ATP = adenosine triphosphate; AMP = adenosine monophosphate; PPi = pyrophosphate; ΔthyA = thymidylate synthase knock out.
Intestinal Degradation of Oxalate Throughout GI Tract Could Enhance Oxalate Lowering
Engineered Strain SYNB8802 Consumes Oxalate and Produces Formate In Vitro
Figure 2: In Vitro 13C-oxalateconsumption and 13C-formateproduction. EcN and SYNB8802 were grown and incubated statically and supernatant samples were removed at 30 and 60 minutes to determine the concentrations of 13C-oxalate and 13C-formate by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Statistical analysis was performed using two-way repeated measures analysis followed by Sidak's multiple comparison test. **p< 0.01, **** p< 0.0001.
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Synlogic Inc. published this content on 23 August 2021 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 23 August 2021 17:23:07 UTC.
Synlogic, Inc. is a biopharmaceutical company advancing novel therapeutics to transform the care of serious diseases. The Company is focused on rare metabolic disorders, with its lead program, labafenogene marselecobac (SYNB1934), studied in Synpheny-3, a global, pivotal Phase 3 study for patients with phenylketonuria (PKU), and SYNB1353, a potential treatment for homocystinuria (HCU). The Company's early-stage pipeline includes product candidates for enteric hyperoxaluria, gout, and cystinuria, and has been fueled by a reproducible, proprietary approach that creates gastrointestinal (GI)-restricted, oral medicines with new enzymatic pathways designed to consume or produce specific biological targets. It designs, develops and manufactures these drug candidates, which are produced by applying genetic engineering to well-characterized probiotics. The Companyâs preclinical work includes additional metabolic disease research.
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